Diabetic nephropathy is the leading cause of end-stge renal disease (ESRD) in the United States. In addition to significant morbidity, diabetic ESRD heralds increased mortality with more than 50% of patients dying within two years of starting dialysis. There is strong evidence that diabetic nephropathy is genetically determined as it aggregates in families. This proposal is submitted in response to RFA-DK-99-005. We propose to study the genetics of diabetic nephropathy in Hispanics with type 2 diabetes. This proposal will focus on Hispanics because they have a strong propensity for development of type 2 diabetes and diabetic nephropathy, making them ideal for genetic studies. This proposal comprises two components. In the first component, we will use both qualitative and quantitative genetic approaches. For qualitative analysis, both concordant relative-pair and discordant sibpair approaches will be used and families will be ascertained through a with diabetes and advanced diabetic renal disease. For quantitative analyses, albuminuria and creatine clearance will be utilized as quantitative traits and sibpairs will be ascertained through a proband with type 2 diabetes. For quantitative analysis, albuminuria and creatine clearance will be utilized as quantitative traits and sibpairs will be ascertained through a proband with type 2 diabetes. The second component is a pharmacogenetic study that aims at evaluating the relation between genetic polymorphisms and the response of nephropathy to angiotensin converting enzyme (ACE) inhibitors. Successful completion of this project will result in the identification of genes that confer susceptibility to diabetic nephropathy. Characterization of the products of these genes will enhance our understanding of the pathogenesis of diabetic renal disease and lead to development of new preventive and therapeutic strategies. Moreover, availability of genetic markers for diabetic nephropathy will allow early identification of patients at risk who should be targeted for intensive glycemic and blood pressure control. The pharmacogenetic component of this proposal will yield new information about the relation between genetic polymorphisms and the response to therapy with ACE inhibitors. Thus, patients who are not likely to respond can be identified early in the course of the disease and treated with alternative medications such as angiotensin II receptor blockers combined with strict glycemic control. Finally, studying Hispanics will provide information which we now lack regarding the pathogenesis and genetics of diabetic nephropathy in this rapidly growing segment of the population. Achieving the goals of this proposal will culminate in a marked reduction in the incidence of diabetic ESRD with a tremendous human and socioeconomic impact.